Depakin chrono - instructions for use, doses, side effects, contraindications

active ingredients: sodium valproate - 199.8 mg, valproic acid - 87.0 mg; Excipients: methylhydroxypropylcellulose 4000 mPa.s (hypromellose) 105.6 mg, ethylcellulose (20 mPa.s) 7.2 mg, sodium saccharate 6.0 mg. silicon dioxide colloidal hydrated - 32.4 mg, methylhydroxypropylcellulose 6 mPa.s (hypromellose) - 4.8 mg, 30% dispersion of polyacrylate - 16.0 mg, macrogol 6000 - 4.8 mg, talc - 4.8 mg, titanium dioxide - 0.8 mg.

In 1 tablet Depakin® chrono with a dosage of 500 mg contains:

active ingredients: sodium valproate - 333 mg, valproic acid - 145.0 mg;

Excipients: silicon dioxide colloidal anhydrous 4.0 mg, methyl hydroxypropylcellulose 4000 mPa.s (hypromellose) 176.0 mg, ethyl cellulose (20 mPa.s) 12.0 mg, sodium saccharinate 10.0 mg, silicon dioxide colloidal hydrated - 50.0 mg, methylhydroxypropyl cellulose 6 mPa.s (hypromellose) 7.2 mg, 30% dispersion of polyacrylate 24.0 mg, macrogol 6000 7.2 mg, talc 7.2 mg, titanium dioxide 1.2 mg.

Description:

Oblong coated tablets, almost white, with a risk on both sides.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug, which has central muscle relaxant and sedative effect.

It shows antiepileptic activity in various types of epilepsy.

The main mechanism of action, apparently, is associated with the action of valproic acid on the GABAergic system: an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and activation of GABA-ergic transmission.

Pharmacokinetics:

Absorption

The bioavailability of sodium valproate and valproic acid when administered is close to 100%.

When taking Depakin® chrono 500 mg tablets at a dose of 1000 mg / day, the minimum plasma concentration (C_min) is 44.7 ± 9.8 μg / ml, and the maximum plasma concentration (FROM_max) is 81.6 ± 15.8 μg / ml. The time to reach the maximum concentration (T_max) is 6.58 ± 2.23 hours. Equilibrium concentration is achieved within 3-4 days of regular intake of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg / l.If the need to achieve higher plasma concentrations is warranted, the ratio of expected benefits and the risk of side effects, especially dose-dependent, should be weighed carefully, since at concentrations above 100 mg / l, side effects are expected to increase until the development of intoxication. At plasma concentrations above 150 mg / l, a dose reduction is required.

Distribution

The volume of distribution depends on the age and is usually 0.13-0.23 l / kg body weight or in young people 0.13-0.19 l / kg body weight.

Communication with blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the association with plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid may increase to 8.5-20%.

With hypoproteinemia, the total concentration of valproic acid (free + bound to plasma proteins of the fraction) may not change, but may also decrease due to an increase in the metabolism of free valproic acid fraction (not associated with blood plasma proteins).

Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in CSF is 10% of the corresponding serum concentration.

Valproic acid penetrates the breast milk of nursing mothers. In the state of achieving an equilibrium concentration of valproic acid in the serum, its concentration in breast milk is from 1% to 10% of its serum concentration.

Metabolism

Metabolism is carried out in the liver by glucuronation, as well as beta, omega, and omega-1 oxidation. More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on the enzymes that enter the metabolic system of cytochrome P450: unlike most others antiepileptic drugs, valproic acid does not affect the extent of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Excretion

Valproic acid is mainly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged.

Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

The half-life is 15-17 hours. When combined with antiepileptic drugs that induce microsomal enzymes of the liver, the plasma clearance of valproic acid increases, and the half-life decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes with other antiepileptic drugs.

The values of the half-life in children over 2 months of age are close to those of adults.

In patients with liver disease, the half-life of valproic acid increases.

In case of an overdose, an increase in the half-life of up to 30 hours was observed.

Hemodialysis is affected only by the free fraction of valproic acid in the blood (10%).

Peculiarities of pharmacokinetics in pregnancy

With an increase in the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug in a constant dose, it is possible to reduce the serum concentrations of valproic acid.In addition, during pregnancy, the relationship of valproic acid with blood plasma proteins can change, which may lead to an increase in the serum content of the free (therapeutically active) fraction of valproic acid.

In comparison with the form covered with enteric-coated shell, the form of prolonged action in equivalent doses is characterized by the following:

- absence of delayed intake after receiving;

- prolonged absorption:

- identical bioavailability;

- a smaller value of C_m_a_x (decrease in C_m_a_x by about 25%), but with a more stable plateau phase from 4 to 14 hours after administration;

- a more linear correlation between the dose and concentration of the drug in plasma.

Indications:

Have adults:

- For the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs).

- For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs).

- For the treatment and prevention of bipolar affective disorders.

Have children:

- For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs).

Contraindications:

- Hypersensitivity to sodium valproate, valproic acid, semlariate valproate, valpromide or to any of the excipients of the drug;

- acute hepatitis;

- chronic hepatitis;

- severe liver disease (especially drug-induced hepatitis) in the patient's and / or close relatives' anamnesis;

- severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;

- severe violations of the liver or pancreas;

- hepatic porphyria;

- established mitochondrial diseases caused by mutations of the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlohera syndrome, and suspected diseases caused by defects of the γ-polymerase in children under the age of two (refers to the use of medicinal forms of the drug Depakin®, which are intended for admission by children) (see section "Special instructions");

- patients with established disorders of the carbamide cycle (urea cycle) (see section "Special instructions");

- combination with mefloquine;

- combination with preparations of St. John's wort;

- Children under 6 years of age (risk of falling into the airway during swallowing).

Carefully:

- With liver and pancreatic disease in history;

- at pregnancy (see sections "Application at pregnancy and in the period of thoracal feeding", "the Way of application and a dose");

- with congenital fermentopathy;

- when oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia).

- with renal failure (dosage correction is required);

- with hypoproteinemia (see sections "Pharmacokinetics", "Method of administration and dose");

- with simultaneous administration of several anticonvulsants (because of the increased risk of liver damage);

- with the simultaneous use of drugs that provoke convulsive seizures or reduce the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butosterophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking convulsive seizures);

- with the simultaneous administration of neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines (the possibility of potentiating their effects);

- with simultaneous administration of phenobarbital, primidon, phenytoin, lamotrigine, zidovudine, felbamate, olanzapine, propofol, aztreonama, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, especially in children, protease inhibitors (lopinavir, ritonavir ), colestyramine (in connection with pharmacokinetic interactions at the level of metabolism or at the level of communication with blood plasma proteins, it is possible to change plasma concentrations or these drugs and / or valproic acid slots, for more details see the section "Interaction with other medicines");

- with the simultaneous use of carbamazepine (the risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid);

- with simultaneous application of topiramate or acetazolamide (risk of encephalopathy);

- in patients with insufficiency carnitine palmitoyltransferase (CBT) type II (higher risk of rhabdomyolysis with valproic acid).

Pregnancy and lactation:

Pregnancy

Depakin® Chrono should not be used in children and adolescent females, women of childbearing age and in pregnant women, unless other methods of treatment are ineffective or not tolerated by the patient.

Pregnant women should make every effort to translate the patient into appropriate alternative treatment, if possible, before conception.

The risk associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia may pose a particular risk for both the mother and the fetus, in connection with the possibility of a lethal outcome.

The risk associated with the use of the drug Depakin^® chrono during pregnancy Experimental studies of reproductive toxicity, conducted in mice, rats and rabbits, demonstrated the presence in valproic acid of teratogenic actions.

Congenital malformations

The available clinical data demonstrated a high incidence of small and severe developmental defects, in particular, neural tube defects, craniofacial deformities, developmental limb and cardiovascular malformations, hypospadias, and multiple malformations affecting various organ systems in children , born to mothers who took valproic acid during pregnancy, compared with their frequency when taking a number of other antiepileptic drugs during pregnancy. Thus, the risk of congenital malformations in children born to mothers with epilepsy who received monotherapy with valproic acid during pregnancy was approximately 1.5, 2.3, 2.3, and 3.7 times higher, compared with phenytoin alone, carbamazepine, phenobarbital and lamotrigine, respectively.

The meta-analysis data, including register and cohort studies, showed that the incidence of congenital malformations in children born to mothers with epilepsy who received monotherapy with valproic acid during pregnancy was 10.73% (95% confidence interval of 8.16- 13.29). This risk is greater than the risk of severe congenital malformations in the general population of 2-3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk.

Disorders of mental and physical development

It is shown that the intrauterine effect of valproic acid can have undesirable effects on the mental and physical development of children exposed to such effects. Apparently, this risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk. The exact gestational period for the risk of these effects is not established, and the risk is not excluded throughout the pregnancy.

Studies of preschool children,exposed to intrauterine exposure to valproic acid, showed that up to 30-40% of such children had early developmental delays (such as delayed walking and speech retardation), and lower intellectual abilities, poor speech skills (speech and understanding of speech) and memory problems.

Coefficient of mental development (index IQ), defined in children at the age of 6 years with an anemia of intrauterine exposure to valproate, was an average of 7-10 points lower, than in children exposed to intrauterine exposure to other antiepileptic drugs. Although the role of other factors that could undesirably affect the intellectual development of children exposed to intrauterine effects of valproic acid can not be ruled out, it is obvious that in such children the risk of intellectual disorders may be independent of the mother's IQ index.

Data on long-term outcomes are limited.

There is evidence that children exposed to intrauterine effects of valproic acid have an increased risk of developing a spectrum of autistic spectrum disorders (approximately a threefold increase in risk),including children's autism (approximately fivefold increase in risk). Limited data suggest that children who have been exposed in utero to valproic acid have a high likelihood of developing Attention Deficit / Hyperactivity Disorder (ADHD).

Monotherapy with valproic acid and combination therapy with the inclusion of valproic acid are associated with an unfavorable outcome of pregnancy, but according to available data, combined antiepileptic therapy including valproic acid is associated with a higher risk of adverse pregnancy outcome compared to valproic acid monotherapy (ie, risk the development of violations in the fetus is less when using valproic acid in monotherapy).

The risk factors for the development of fetal malformations are: a dose of more than 1000 mg / day (however, a lower dose does not exclude this risk) and the combination of valproic acid with other anticonvulsant drugs.

In connection with the foregoing, the drug Depakin® chrono should not be used in pregnancy and in women with childbearing potential without extreme necessity, that is,its use is possible only in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The need to use the drug Depakin® chrono or the possibility of refusing its use should be decided before the drug is started or revised if the woman taking the drug Depakin® chrono is planning a pregnancy.

Women should be informed of the need for pregnancy planning and control over the course of pregnancy.

Women with childbearing potential should use effective methods of contraception during treatment with the drug Depakin^® chrono.

Women with childbearing potential should be informed of the risks and benefits of using valproic acid during pregnancy.

If a woman is planning a pregnancy or has a pregnancy diagnosed, valproic acid should be reassessed depending on the indications (see below).

- When bipolar disorder is indicated, consideration should be given to stopping treatment with valproic acid.

- When epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio.If after a reassessment of the ratio of benefit and risk, treatment with Depakin^® chrono should still be continued during pregnancy, it is recommended to apply it in the minimum effective daily dose divided into several methods. It should be noted that during pregnancy, the use of dosage forms of the sustained release preparation is more preferable than other dosage forms.

If possible, even before the onset of pregnancy, you should also start taking folic acid (at a dose of 5 mg per day), since folic acid can reduce the risk of developing neural tube defects. However, the data available at present do not confirm its preventive action against congenital malformations arising from the action of valproic acid.

A special prenatal diagnosis should be performed (including in the third trimester of pregnancy) to identify possible defects in the formation of the neural tube or other fetal malformations, including detailed ultrasound.

Before childbirth

Before delivery, the mother should conduct coagulation tests, in particular, the determination of the number of platelets, the concentration of fibrinogen and clotting time (activated partial thromboplastin time: APTT).

Risk for newborns

There have been reports of the development of single cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia. hypofibrinogenemia and / or a decrease in the content of other coagulation factors. Also reported on the development of afibrinogenemii, which could lead to death. This hemorrhagic syndrome should be distinguished from the vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns whose mothers received treatment with valproic acid during pregnancy, coagulation tests (determine the number of platelets in the peripheral blood, plasma fibrinogen concentration, clotting factors and coagulogram) should be performed.

Reported cases of hypoglycemia in newborns whose mothers took valproic acid during the third trimester of pregnancy.

Hypothyroidism was reported in newborns whose mothers took valproic acid during pregnancy.

In newborns whose mothers took valproic acid in the last trimester of pregnancy, withdrawal can occur (in particular, the appearance of agitation, irritability, hyperreflexia, tremor, hyperkinesia, muscle tone disorders, tremors, seizures and difficulty feeding).

Fertility

In connection with the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, an increase in the concentration of testosterone in the blood, fertility in women may decrease (see the "Side effect" section). In men valproic acid can reduce sperm motility and impair fertility (see section "Side effect"). It is established that these violations of fertility are reversible after discontinuation of treatment.

Breastfeeding period

Excretion of valproic acid in breast milk is low, its concentration in milk is 1-10% of its serum concentration.

There are limited clinical data on the use of valproic acid in breastfeeding, and therefore the use of the drug in this period is not recommended.

Based on literature data and little clinical experience, breastfeeding with Depakin® chrono can be considered, but the profile of side effects of the drug, especially the hematologic disorders caused by it, should be taken into account.

Dosing and Administration:

This drug is intended only for adults and children over 6 years old with a body weight of more than 17 kg!

This dosage form is not recommended for children under 6 years of age (risk of ingestion of the pill in the respiratory tract during swallowing)!

Depakin^® Chrono is a sustained release dosage form of the active ingredient. Prolonged release allows to avoid sharp increases in valproic acid concentration in the blood after taking the drug and longer maintains a constant concentration of valproic acid in the blood during the day.

Long-acting tablets Depakin^® chrono 300 mg / 500 mg can be divided to facilitate the reception of an individual selected dose.

Tablets are taken without crushing or chewing them.

Dosing regimen for epilepsy

The daily dose is selected individually by the attending physician.

It is necessary to select the minimum effective dose to prevent the development of epilepsy attacks (especially during pregnancy). The daily dose should be adjusted according to age and body weight. A stepwise (gradual) increase in the dose is recommended until the minimum effective dose is reached.

There was no clear relationship between the daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined mainly by the clinical response. Determining the concentration of valproic acid in plasma can serve as a supplement to clinical observation if epilepsy is not controlled or there is a suspicion of side effects. The range of therapeutic concentration in the blood is usually 40-100 mg / l (300-700 μmol / l).

When monotherapy the initial daily dose is usually 5-10 mg of valproic acid per kg of body weight,which is then gradually increased every 4-7 days at a rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with prolonged use):

- for children 6-14 years (body weight 20-30 kg) - 30 mg valproic acid / kg body weight (600-1200 mg);

- for adolescents (body weight 40-60 kg) - 25 mg valproic acid / kg body weight (1000-1500 mg);

- for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg body weight (1200-2100 mg).

Although the daily dose is determined depending on the age and body weight of the patient; should take into account a wide range of individual sensitivity to valproate.

If epilepsy can not be controlled at such doses, they can be increased under the control of the patient's condition and the concentration of valproic acid in the blood.

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, do not increase the daily dose above the recommended average daily dose before this time.

The daily dose can be divided into 1-2 administrations, preferably during meals.Use in one dose is possible with well-controlled epilepsy. Most patients who are already taking the dosage form of Depakin®, a non-protracted drug, can be transferred to the dosage form of this long-acting drug immediately or for several days, and patients should continue to take the previously selected daily dose.

For patients who have taken antiepileptic drugs earlier, the transfer to the drug Depakin® chrono should be carried out gradually, reaching the optimal dose of the drug for about 2 weeks. At the same time, the dose of an antiepileptic drug previously taken, especially phenobarbital, is immediately reduced. If previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, monitor the concentrations of valproic acid in the blood within 4-6 weeks after the last dose of these antiepileptic drugs and, if necessary (as the metabolic-inducing effect of these drugs decreases), reduce the daily dose valproic acid.

If necessary, combinations of valproic acid with other antiepileptic drugs should be added to the treatment gradually (see "Interaction with other drugs").

Dosing regimen for manic episodes with bipolar disorders

Adults

The daily dose is selected individually by the attending physician.

The recommended initial daily dose is 750 mg. In addition, in clinical trials, the initial dose, which was 20 mg of sodium valproate per kg of body weight, also showed an acceptable safety profile.

Release forms with sustained release can be taken once or twice a day. The dose should increase as quickly as possible before reaching the minimum therapeutic dose, which causes the desired clinical effect.

The average daily dose is in the range of 1000-2000 mg of sodium valproate. Patients taking a daily dose above 45 mg / kg / day should be under close medical supervision.

Continuation of treatment of manic episodes in bipolar disorders should be carried out by taking an individually selected minimum effective dose.

Children and teens

The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorders in patients younger than 18 years of age have not been evaluated.

The use of the drug in patients of special groups

Children and adolescents female, women with childbearing potential and pregnant women

Treatment with Depakin^® chrono should be started under the supervision of a specialist with experience in the treatment of epilepsy and bipolar disorders. Treatment should be started only if other treatments are ineffective or not tolerated (see "Special instructions", "Use during pregnancy and during breastfeeding"), and with regular review of treatment, the ratio of benefit and risk should be carefully re-evaluated . Preferred is the use of drugs Depakin^® in monotherapy and at the lowest effective doses and, if possible, in sustained-release dosage forms. During pregnancy, the daily dose should be divided, at least, into 2 single doses.

Elderly patients

Although elderly patients have changes in the pharmacokinetics of valproic acid,they have limited clinical relevance and the dose of valproic acid in elderly patients should be selected in accordance with the achievement of control over epileptic seizures.

Renal insufficiency and / or hypoproteinemia

In patients with renal insufficiency and / or hypoproteinemia, the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and, if necessary, to reduce the dose of valproic acid, guided by the dose selection, mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction associated with plasma proteins, together) to avoid possible errors in the selection of the dose.

Side effects:

To indicate the incidence of adverse reactions (HP) The classification of the World Health Organization is used: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0.1% and <1%; rarely ≥0.01% and <0.1%; very rarely <0.01%; frequency is unknown (when, according to available data, to estimate the frequency of development HP does not seem possible).

Congenital, hereditary and genetic disorders

Teratogenic risk (see section "Application during pregnancy and during breastfeeding").

Violations of the blood and lymphatic system

Purely: anemia, thrombocytopenia (see section "Special instructions").

Infrequently: pancytopenia, leukopenia, neutropenia.

Leukopenia and pancytopenia can be, with or without bone marrow depression. After the drug is stopped, the blood picture returns to normal.

Rarely: disorders of bone marrow hematopoiesis. including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; a decrease in the content of clotting factors (at least one), a deviation from the norm of the clotting parameters (such as an increase in prothrombin time, an increase in activated partial thromboplastin time, an increase in thrombin time, an increase in INR [international normalized ratio]) (see " pregnancy and during breastfeeding "and" Special instructions ").

The emergence of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct a survey.

Laboratory and instrumental data

Rarely: biotin deficiency / biotinidase deficiency.

Disturbances from the nervous system

Very clean: tremor.

Often: extrapyramidal disorder, stupor *, drowsiness, convulsions *, memory impairment, headache, nystagmus; dizziness (with intravenous administration, dizziness may occur within a few minutes and pass spontaneously within a few minutes).

Infrequently: coma *, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia, heavier seizures (see section "Special instructions").

Rarely: reversible dementia, combined with reversible cerebral atrophy, cognitive disorders.

Frequency unknown: sedation.

* Stupor and lethargy sometimes lead to transient coma / encephalopathy and were either isolated, or combined with increased frequency of convulsive attacks against the background of treatment, and also decreased with withdrawal of the drug or with a decrease in its dose. Most of these cases have been described against a background of combined therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

Hearing disorders and labyrinthine disorders

Often: reversible and irreversible deafness.

Disturbances on the part of the organ of sight

Frequency unknown: diplopia.

Disturbances from the respiratory organs, thorax and mediastinum

Infrequently: pleural effusion.

Disorders from the digestive system

Often: nausea.

Often: vomiting, gum changes (mainly gum hyperplasia), stomatitis, epigastric pain, diarrhea, which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy. Frequent reactions from the digestive system can be reduced by taking the drug during or after a meal.

Infrequently: pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment: in the case of acute pain in the abdomen, it is necessary to monitor the activity of serum amylase, see section "Special instructions").

Frequency unknown: abdominal cramps, anorexia, increased appetite.

Disorders from the kidneys and urinary tract

Infrequently: renal insufficiency.

Rarely: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of affection of proximal renal tubules with violation of tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the development mechanism of which is still unclear.

Disturbances from the skin and subcutaneous tissues

Often: hypersensitivity reactions, for example, urticaria, pruritus; transitory (reversible) and / or dose-dependent pathological hair loss (alopecia), including adrogenic alopecia against the background of developed hyperandrogenia, polycystic ovary (see below subsections "Genital and breast disorders" and "Endocrine system disorders"), and also alopecia against the background of developed hypothyroidism (see below section "Endocrine system disorders"), violations from the nails and the nail bed.

Infrequently: angioedema, rash, hair disorders (such as abnormal hair structure, hair color changes, abnormal hair growth [disappearance of waviness and curly hair, or vice versa, appearance of curly hair in persons with initially straight hair]).

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

Disturbances from musculoskeletal and connective tissue

Infrequently: reduction of bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakin® for a long time. The mechanism of the influence of Depakin® preparations on the metabolism of bone tissue is not established.

Rarely: systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see sections "With caution", "Special instructions").

Disorders from the endocrine system

Infrequently: syndrome of inadequate secretion of antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or increase in androgen concentrations in the blood).

Rarely: hypothyroidism (see section "Application during pregnancy and during breast-feeding").

Disorders from the metabolism and nutrition

Often: hyponatremia, weight gain (the increase in body weight should be carefully monitored, since weight gain is a factor contributing to the development of the polycystic ovary syndrome).

Rarely: hyperammonemia * (see section "Special instructions"), obesity.

* There may be cases of isolated and moderate hyperammonemia without changing liver function indicators that do not require discontinuation of treatment.Also reported the emergence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurologic symptoms), which required the discontinuation of valproic acid and an additional examination (see section "Special instructions").

Benign, malignant and vague tumors (including cysts and polyps)

Rarely: myelodysplastic syndromes.

Vascular disorders

Often: bleeding and hemorrhage (see sections "Special instructions" and "Use during pregnancy and during breastfeeding").

Infrequently: vasculitis.

General disorders and changes in the site of administration

Infrequently: hypothermia, minor peripheral edema.

Disturbances from the liver and bile ducts

Often: liver damage: abnormal liver function indicators, such as a decrease in the prothrombin index, especially in combination with a significant decrease in fibrinogen and clotting factors, an increase in the concentration of bilirubin and an increase in the activity of "liver" transaminases in the blood; liver failure,in exceptional cases, fatal; it is necessary to monitor patients for possible violations of the baking function (see section "Special instructions").

Violations of the genitals and mammary gland

Often: dysmenorrhea.

Infrequently: amenorrhea.

Rarely: male infertility, polycystic ovary.

Frequency unknown: irregular menstruation, increased mammary glands, galactorrhea.

Disorders of the psyche

Often: a state of confusion, hallucinations, aggressiveness *, agitation *, attention violation *; Depression (when combining valproic acid with other anticonvulsants).

Rarely: behavioral disorders *, psychomotor hyperactivity *, learning disabilities *; depression (with monotherapy with valproic acid).

* Undesirable reactions, mainly observed in patients of childhood.

Overdose:

Clinical manifestations of acute massive overdose usually occur in the form of coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive lowering of arterial pressure, and vascular collapse / shock.

Cases of intracranial hypertension associated with edema of the brain were described. The presence of sodium in the composition of valproic acid preparations during their overdose can lead to the development of hypernatremia.

With a massive overdose, a lethal outcome is possible, but usually the prognosis is favorable when overdosed.

Symptoms of overdose may vary, reported on the development of convulsive seizures with very high plasma concentrations of valproic acid.

Treatment of overdose

Emergency care for an overdose in a hospital should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective to receive activated charcoal, including its administration through a nasogastric tube. It is required to monitor the state of the cardiovascular and respiratory system and maintain an effective diuresis. It is necessary to monitor the liver and pancreas. If breathing is depressed, artificial ventilation may be required. In some cases, naloxone. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Interaction:

The effect of valproic acid on other drugs

Neuroleptics, inhibitors monoamine oxidase (MAO), antidepressants, benzodiazepines

Valproic acid may potentiate the effects of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, when they are used simultaneously with valproic acid, careful medical supervision and, if necessary, dosage adjustment are recommended.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases the plasma concentrations of phenobarbital (due to a decrease in its hepatic metabolism), in connection with which the development of sedative action of the latter, especially in children, is possible. Therefore, careful medical supervision of the patient during the first 15 days of combination therapy with immediate reduction of the dose of phenobarbital in case of development of sedation and, if necessary, determination plasma concentrations of phenobarbital.

Primidone

Valproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation); at long-term treatment, these symptoms disappear. A thorough clinical observation of the patient is recommended, especially at the beginning of the combination therapy (first 15 days), with correction of the primidon dose, if necessary.

Phenytoin

Valproic acid reduces the total plasma concentrations of phenytoin. Besides, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of an overdose (valproic acid expels phenytoin from the connection with plasma proteins and slows down its hepatic catabolism). Therefore, with the simultaneous use of phenytoin and valproic acid, careful clinical observation of the patient is recommended, and when determining the concentrations of phenytoin, determine the concentration of its free fraction in the blood.

With the simultaneous use of valproic acid and carbamazepine, an increase in the plasma concentration of the active metabolite of carbamazepine with signs of overdose is possible.There have been reports of the occurrence of clinical manifestations of carbamazepine toxicity, since valproic acid can potentiate the toxic effects of carbamazepine. Clinical monitoring of such patients is recommended, especially at the beginning combined therapy with appropriate dose adjustment of carbamazepine if necessary.

Lamotrigine

Valproic acid slows the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 2 times. This interaction can lead to an increase in lamotrigine toxicity, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, a thorough clinical observation and, if necessary, correction (reduction) of the dose of lamotrigine.

Zidovudine

Valproic acid can increase plasma concentrations of zidovudine, which increases the toxicity of zidovudine, especially hematologic effects, by slowing its metabolism with valproic acid. It is necessary to constantly monitor and monitor laboratory indicators.A blood test should be done to exclude the development of anemia within the first two months of the combination therapy.

Felbamat

Valproic acid can reduce the average clearance value of felbamate by 16%. Valproic acid can reduce plasma concentrations of olanzapine.

Rufinamide

Valproic acid can lead to an increase in the plasma concentration of rubinamide. This increase depends on the concentration of valproic acid in the blood. Care should be taken, especially in children, since this effect is more pronounced in this population.

Propofol

Valproic acid can lead to an increase in plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when it is used concomitantly with valproic acid.

Nimodipine (for oral administration and, for extrapolation, solution for parenteral administration)

Strengthening the hypotensive effect of nimodipine due to the simultaneous use of nimodipine with valproic acid can increase plasma concentrations of nimodipine by 50% (by inhibiting the metabolism of nimodipine with valproic acid).

Temozolomide

Simultaneous administration of temozolomide with valproic acid leads to mild, but statistically significant, decrease in the clearance of temozolomide.

The effect of other drugs on valproic acid

Pantiepileptic drugs, capable of induce microsomal liver enzymes (including phenytoin, primidon, phenobarbital, carbamazepine) reduce the plasma concentrations of valproic acid. In the case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

The concentration of valproic acid metabolites in the serum can be increased if it is used simultaneously with phenytoin or phenobarbital. Therefore, patients receiving treatment with these two drugs should be carefully monitored for signs and symptoms of hyperammonemia, since some valproic acid metabolites can inhibit urea enzymes (urea cycle).

Azrethon

The risk of seizures is due to a decrease in the concentration of valproic acid in the blood plasma.Clinical observation, determination of plasma concentrations of valproic acid and possible dose adjustment An anticonvulsant during treatment with this antibacterial drug and after its cessation.

Felbamat

When combined with felbamate and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, the plasma the concentration of valproic acid. Plasma concentrations of valproic acid should be monitored. Clinical observation and control of laboratory parameters are necessary, correction of valproate dose during treatment and after stopping felbamate administration is possible.

Carbamazepine

It is possible to reduce the plasma concentration of valproic acid due to the acceleration of carbamazepine by its metabolism in the liver. Clinical observation, determination of plasma concentrations and possible correction of the doses of both anticonvulsants are necessary.

Lamotrigine

It is possible to increase the concentration of lamotrigine in plasma (due to the slowing of valproate metabolism of lamotrigine in the liver).

If simultaneous use of these drugs is required, clinical control is required.

Meflokhin

Meflokhin accelerates the metabolism of valproic acid and is itself capable of causing seizures, so when they are used simultaneously, an epileptic fit may develop.

Preparations of St. John's Wort

With the simultaneous use of valproic acid and preparations of St. John's wort, a possible reduction in anticonvulsant efficacy of valproic acid is possible.

Preparations that have a high and strong bond with plasma proteins (acetylsalicylic acid)

In the case of concomitant use of valproic acid and preparations having a high and strong bond with plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free valproic acid fraction.

Indirect anticoagulants, including warfarin and other coumarin derivatives

With simultaneous use of valproic acid and anticoagulants requires careful control of the INR and prothrombin index.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase in the case of simultaneous use of cimetidine or erythromycin (as a result of a slowing of its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem)

Reduction of valproic acid concentrations in the blood with its simultaneous application with carbapenems: for two days of joint therapy, a 60-100% reduction in valproic acid in the blood was observed, which was sometimes associated with the occurrence of seizures. Carbapenems should not be used concomitantly in patients with a selected dose of valproic acid because of their ability to rapidly and rapidly reduce valproic acid concentrations in the blood. If carbapenem treatment can not be avoided, careful monitoring of valproic acid concentrations in the blood should be performed during carbapenem treatment and after it is discontinued.

Rifampicin

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to a loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid with simultaneous application of rifampicin and after its withdrawal.

Inhibitors of proteases

Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid with simultaneous use with it.

Kolyacmiramin

Colestiramine can lead to a decrease in plasma concentrations of valproic acid with simultaneous application.

Other interactions

With topiramate or acetazolamide

The simultaneous use of valproic acid and topiramate or acetazolamide was associated with encephalopathy and / or hyperammonemia. Patients taking these drugs concomitantly with valproic acid should be carefully monitored for symptoms of hyperammonemic encephalopathy.

With quetiapine

The simultaneous use of valproic acid and quetiapine may increase the risk of developing neutropenia / leukopenia.

With estrogen-progestogen drugs

Valproic acid does not have the ability to induce liver enzymes, and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen drugs in women who use hormonal methods contraception.

With ethanol and other potentially hepatotoxic drugs

When used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

With clonazepam

The simultaneous use of clonazepam with valproic acid may lead in a few cases to an increase in the expression of absent status.

With myelotoxic drugs

When they are used simultaneously with valproic acid, the risk of oppression of bone marrow hematopoiesis increases.

Special instructions:

Before starting the use of the drug Depakin^® chronically and periodically during the first 6 months of treatment, especially in patients at risk of developing liver disease, a study of liver function should be performed.

As with the majority of antiepileptic drugs, with the use of valproic acid, a slight increase in the activity of "liver" enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. These patients need a more detailed study of biological indicators, including a prothrombin index, and a dose adjustment of the drug may be required, and if necessary, a re-clinical and laboratory examination.

Before starting therapy or before surgery,as well as spontaneous subcutaneous hematoma or bleeding, it is recommended to determine the time of bleeding, the number of elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

There have been isolated reports of the development of severe liver damage, sometimes fatal. Clinical experience shows that patients at risk are patients taking several antiepileptic drugs at the same time; infants and children younger than 3 years of age with severe seizures, especially in the presence of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients taking salicylates at the same time (since salicylates are metabolized along the same metabolic pathway as valproic acid).

After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient's age increases. In most cases, this liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment, and usually with the use of valproic acid in combination antiepileptic therapy.

Symptoms Suspected of Liver Damage

For early diagnosis of liver damage, clinical monitoring of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk (see above):

- nonspecific symptoms, especially sudden ones, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- the resumption of convulsive seizures in patients with epilepsy.

It is necessary to warn patients or their families (when using the drug by children) that they should immediately report the occurrence of any of these symptoms to the treating doctor. Patients should immediately carry out a clinical examination and a laboratory study of liver function indicators.

Identify

Determination of functional liver samples should be performed before treatment and then periodically during the first 6 months of treatment. Among the usual studies, the most informative studies reflecting the state of protein-synthetic liver function, especially the definition of the prothrombin index.Confirmation of the deviation from the norm of the prothrombin index towards its decrease, especially in combination with deviations from the norm of other laboratory indicators (a significant decrease in fibrinogen and coagulation factors, an increase in bilirubin concentration and an increase in the activity of "liver" transaminases), and the appearance of other symptoms indicating on liver damage (see above), requires discontinuation of the drug Depakin^® chrono. For the purpose of precaution in If patients took salicylates concurrently, their reception should also be discontinued.

Pancreatitis

There are registered rare cases of severe forms of pancreatitis in children and adults that developed regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with a rapid progression of the disease from the first symptoms to the fatal outcome.

Children are at increased risk of developing pancreatitis, with increasing age of the child, this risk is reduced. Risk factors for pancreatitis can be severe seizures, neurological disorders, or anticonvulsant therapy.Hepatic insufficiency, combined with pancreatitis, increases the risk of death.

Patients who experience severe abdominal pain, nausea, vomiting, and / or anorexia should be examined immediately. In case of confirmation of the diagnosis of pancreatitis, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued, and appropriate treatment should be started.

Children and adolescents female, women with childbearing potential and pregnant women

The drug Depakin® Chrono should not be used in children and adolescent females, women with childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenic effects and mental and physical developmental disorders in children who have been in utero exposed to valproic acid. The benefit / risk ratio should be carefully reassessed in the following cases: during regular revision of treatment, when the girl reaches puberty and, as a matter of urgency, if the woman taking valnroic acid is planning or becoming pregnant.

During treatment with valproic acid, women with childbearing potential should use reliable methods of contraception, and they should be informed of the risks associated with taking the drug Depakin® chrono during pregnancy (see section "Use during pregnancy and during breastfeeding"). To help the patient understand these risks, the doctor who prescribes valproic acid should provide the patient with comprehensive information about the risks associated with taking the drug Depakin® chrono during pregnancy.

In particular, the physician prescribing valproic acid should make sure that the patient understands:

- the nature and magnitude of the risks associated with the use of valproic acid during pregnancy, particularly the risks of teratogenic effects, as well as the risks of mental and physical developmental disorders;

- the need to use effective contraception;

- the need for regular revision of treatment;

- the need for urgent consultation with your doctor if she suspects she has become pregnant, or when she suggests the possibility of pregnancy.

A woman planning a pregnancy should definitely try, if possible, to switch to alternative treatment before she attempts to conceive (see "Application in pregnancy and during breastfeeding"). Treatment with valproic acid should be continued only after a doctor who has experience in the treatment of epilepsy and bipolar disorders, will reassess her the relationship between benefit and risks from treatment.

Suicidal thoughts and attempts

There have been reports of suicidal thoughts and attempts in patients taking antiepileptic drugs for certain indications. Meta-analysis of randomized placebo-controlled trials antiepileptic drugs also showed an increased risk of suicidal thoughts and attempts at 0.19% in all patients taking antiepileptic drugs (including an increase in this risk by 0.24% in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.

Therefore, patients taking the drug Depakin® chrono should be constantly monitored for suicidal thoughts and attempts, as well.in case of their occurrence, it is necessary to conduct appropriate treatment. Patients and caregivers are advised when the patient has suicidal thoughts or attempts to immediately consult a doctor.

Carbapenems

Simultaneous use of carbapenems is not recommended (see section "Interaction with other drugs").

Patients with established mitochondrial diseases or suspected of them

Valproic acid can initiate or weight the manifestations of the patient's mitochondrial diseases caused by mitochondrial DNA mutations, as well as the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations of the gene encoding the γ-polymerase (POLG); for example, patients with Alpers-Huttenlohera syndrome with valproic acid associated a higher incidence of acute hepatic impairment and liver-related deaths. Diseases caused by defects of the γ-polymerase,may be suspected in patients with a family history of such diseases or with suspicious symptoms, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia , ophthalmoplegia or complicated migraine with visual (occipital) aura and others.

In accordance with modern clinical practice for the diagnosis of such diseases should lead the test for mutations of the γ-polymerase gene (POLG) (see section "Contraindications").

Increased seizures

As with the use of other antiepileptic drugs, when receiving valproic acid in some patients, a reversible increase in the frequency and severity of convulsive seizures (including the development of epileptic status) or the appearance of new types of convulsions was observed, instead of improving. In case of heavier seizures, patients should immediately consult with their doctor (see "Side effect").

Children (information refers to the dosage form of Depakin®, which can be taken by children under the age of three)

Children under the age of three years, if necessary, use the drug, its use in monotherapy and in the recommended dosage form for children is recommended. In this case, before the start of treatment should weigh the ratio of the potential benefits of valproic acid and the risk of liver damage and the development of pancreatitis when it is used.

Children under 3 years of age should avoid the simultaneous use of valproic acid and salicylates due to the risk of toxic effects on the liver.

Renal insufficiency

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. In case of impossibility of monitoring plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme insufficiency of carbamide cycle (urea cycle)

If the enzyme deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Such patients described several cases of hyperammonemia with a stupor or coma.In these cases, metabolic studies should be performed prior to treatment with valproic acid (see "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), a history of lethargy or coma, a mental retardation or a family history of the death of a newborn or child prior to treatment with valproic acid, studies of metabolism should be conducted, ammonia (the presence of ammonia and its compounds in the blood) on an empty stomach and after a meal (see "Contraindications").

Patients with systemic lupus erythematosus

Although it has been shown that during the treatment with the drug Depakin® chrono, the immune system functions are extremely rare, the potential benefit from its use should be compared with the potential risk when using the drug in patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mostly dietary, should be taken to minimize this phenomenon.

Patients with diabetes mellitus

Given the potential for adverse effects of valproic acid on the pancreas, the use of the drug in patients with diabetes should carefully monitor the concentration of glucose in the blood. In the study of urine for the presence of ketone bodies in patients with diabetes mellitus, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partially in the form of ketone bodies.

Patients, infected with the human immunodeficiency virus (HIV)

AT in vitro it was found that valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact, if any, is unknown. In addition, the value of these data obtained in the studies in vitro, for patients receiving maximum suppressive antiretroviral therapy. However, these data should be taken into account when interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.

Patients with existing insufficiency carnitine palmitoyltransferase (CBT) tine II

Patients with existing type II CPT deficiency should be warned about a higher risk of developing rhabdomyolysis with valproic acid.

Ethanol

During treatment with valproic acid, ethanol is not recommended.

Other special instructions

The inert matrix of the drug Depakin® chrono (sustained-release preparation) bonds with the nature of its excipients is not absorbed in the gastrointestinal tract; After the release of the active substances, the inert matrix is excreted with caloric masses.

In one tablet of the drug Depakin® chrono 300 mg contains 1.2 mmol (27.6 mg) of sodium. In one tablet of the drug Depakin^® Chrono 500 mg contains 2 mmol (46.1 mg) of sodium. This need to be taken into account in patients who follow a strict diet with a low sodium content.

Effect on the ability to drive transp. cf. and fur:

Patients should be warned about the risk of developing drowsiness, especially if combined anticonvulsant therapy is used or when the drug Depakin® chrono is combined with benzodiazepines (see section "Interaction with other drugs").

Form release / dosage:

The tablets of the prolonged action covered with a cover, 300 mg and 500 mg.

Packaging:

Long-acting tablets, coated with 300 mg.

For 50 tablets in a polypropylene bottle, closed with a plastic stopper, with a desiccant.

2 bottles together with instructions for use are placed in a cardboard box.

Long-acting tablets, coated with 500 mg.

For 30 tablets in a polypropylene bottle, closed with a plastic stopper, with a desiccant.

1 bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store in a dry place, at a temperature below 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not take the drug after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013004 / 01

Date of registration:29.03.2012

Expiration Date:Unlimited

The owner of the registration certificate:Sanofi Winthrop IndustrySanofi Winthrop Industry France

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp23.04.2017

Illustrated instructions

Instructions

Depakin® chrono (Depakine® chrono)